Dialysis is primarily used to provide an artificial replacement for lost kidney function in patients with kidney failure. Patients have different dialysis options. The most common type of dialysis in the United States is hemodialysis. Vascular access, which provides repeated, reliable access to the bloodstream, is required for hemodialysis. The optimal form of hemodialysis vascular access is the arteriovenous fistula (AVF), a conduit surgically created in the arm connecting an artery and a vein, which takes several weeks (up to 12) to properly mature for hemodialysis. Unfortunately, up to 60% of AVF fail to mature properly to sustain chronic hemodialysis.
The primary contributor to AVF nonmaturation is intimal hyperplasia (IH). The tunica intima (intima) is an inner layer of cells in an artery or vein. Intimal hyperplasia (IH) refers to an increase in number or size of cells in the intima resulting in the gross enlargement and potential closing of the artery and/or vein. IH in dialysis arteriovenous (AV) access is accelerated and can result in vessel narrowing leading to reduced AV access blood flow or thrombosis. Consequently, end-stage renal disease (ESRD) patients may require an access intervention every 3-6 months to reestablish and maintain patency and, over time, can exhaust sites for all AV access options in the upper extremities. Currently, there is no effective therapy to treat IH in ESRD patients. An individual patient's susceptibility to IH varies, therefore the ability to predict whether a patient is at greater risk of AVF nonmaturation with consequent increased central venous catheter time as a bridge to AVF maturation, or multiple AV access surgeries, would be beneficial to provide patient's options, such as peritoneal dialysis or AV graft use.
Angiotensin II contributes to IH. Interruption of the renin-angiotensin system with ACE inhibition has been investigated, but does not attenuate IH in humans. Chymase is an ACE-independent angiotensin II-forming enzyme present in blood vessels and contained in the secretory granules of mast cells. With inflammatory stimulus, chymase is released into the vascular interstitium and forms Angiotensin II independent of ACE. Chymase inhibition in animal models is shown to effectively attenuate IH.